The objectives of the investigations set forth in this proposal are to determine whether: 1) rapid increases in the insulin-sensitivity or insulin-responsiveness occur under physiologic conditions in man; 2) if such changes are mediated by a serum factor(s); and 3) whether changes in the affinity of the insulin receptor contribute to the rapid enhancement in insulin action. A multiphasic approach has been proposed, based on preliminary work that has demonstrated acute increases in insulin-sensitivity and receptor affinity following glucose administration. In the preliminary research, glucose administered orally or I.V. to normal volunteers produced an increase in insulin-sensitivity as measured by the euglycemic clamp. Postglucose serum isolated from the normal volunteers during these studies was incubated with rat adipose tissue, and demonstrated a serum factor that increased insulin-sensitivity and insulin-binding affinity. In other preliminary studies glucose administration to rats produced an acute increase in the insulin-sensitivity and insulin-responsiveness of their adipocytes and increased the affinity of the insulin receptor. The research outlined in this proposal seeks to continue and extend the preliminary investigations noted above. The effects of oral or IV glucose administration on insulin-sensitivity in normal and insulin-resistant subjects will be examined using the euglycemic clamp method. Parallel work will be conducted in a rat model system in which tissues taken after oral or IV glucose loading will be tested for changes in insulin-sensitivity and insulin-binding. Studies are proposed that will attempt to partially characterize the factor(s) in post-glucose human serum that enhances insulin sensitivity and insulin-binding of adipocytes. The results of the proposed investigations should advance the understanding of normal mechanisms that control insulin sensitivity in man and provide new insights pertinent to the pathophysiology underlying certain insulin resistant states.